How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission
1Departments of Psychiatry, Neurology, and Pharmacology, Columbia University Medical Center, Black 308, 650 W. 168 St., New York, NY 10032, USA *Correspondence: email@example.com DOI 10.1016/j.neuron.2011.02.010
The fundamental principle that unites addictive drugs appears to be that eachenhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms that can be involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evokedover basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce nonexocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions about the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, buttheir ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging.
Introduction Addiction is an unusual disease in that it is not a consequence of cellular dysfunction: addictive drugs ‘‘hijack’’ normal learning processes to reinforce their own acquisition. It is further unusual in being a modern disorder. Roy Wise made the observation in thisjournal that ‘‘addiction is quite a recent phenomenon, largely dependent upon the controlled use of ﬁre (smoking), hypodermic syringes (intravenous injection), and the cork and bottle (storage and transportation of alcohol)’’ (Wise, 2000). To more efﬁcient delivery systems, we add the contributions of modern chemists, who isolated active components of psychoactive plants (cocaine and morphine) andinvented easily administered drugs (amphetamine: AMPH, methamphetamine: METH, toluene, and heroin). Addictive drugs exhibit a wide range of structures and actions, but the unifying principle appears to be that they each acutely enhance striatal dopamine (DA) neurotransmission by means that dissociate it from normal drive by environmental cues. Striatal DA levels are normally driven by three majorfactors: (1) neuronal ﬁring, which is chieﬂy modulated by environmental cues via somatodendritic receptors; (2) reuptake by the DA plasma membrane uptake transporter (DAT); and (3) the state of the presynaptic terminal, which controls the number, probability, and size of the quantal events released in response to neuronal activity. Thus, addictive drugs might in principle act (1) by enhancingneuronal ﬁring beyond that normally driven by environmental cues, as do nicotine, opiates, and sedatives; (2) by inhibiting DA reuptake, as does cocaine; (3) by altering release probability from the presynaptic terminal, as do nicotine and opiates. Less predictable from normal synaptic function are the actions of AMPHs, which (4) release DA via reversal of DAT independent of synaptic vesicle fusion(Table 1, Figures 1 and 2). The Concept and Identiﬁcation of Addictive Drugs Deﬁning the set of addictive drugs is elusive in part as it depends on whether society considers them to be destructive. For
628 Neuron 69, February 24, 2011 ª2011 Elsevier Inc.
example, evidence for clinical opium use extends to 5000 B.C. in Sumeria, where it was known as ‘‘joy plant’’; among a horde of opium-relatedartifacts surviving from the ancient Mediterranean is a goddess from Minoan Crete with a poppy crown associated with a vase apparently used for breathing opium vapors (Kritkikos and Papdaki, 1967). Ancient and medieval Greek and Arabic pharmacologists who wrote on opium, including Dioscorides, Galen, and Avicenna (Ibn Sina), mention opium’s clinical use and toxicity but not habit (Tibi, 2006)....